The present invention relates to nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof which have an activity of inhibiting phosphorylation of a platelet-derived growth factor (PDGF) receptor and are useful in treating cell proliferative diseases, such as arteriosclerosis, vascular re-obstruction disease, cancers, glomerulonephritis, and the like.
It is known that PDGF functions as an advancing factor upon cell proliferative diseases, such as arteriosclerosis, vascular re-obstruction after percutaneous transluminal coronary angioplasty or bypass angioplasty, cancers, glomerulonephritis, glomerulosclerosis, psoriasis, articular rheumatism, and the like [Cell, 46: 155-169 (1986), Science, 253: 1129-1132 (1991), Nihon Rinsho, 50: 3038-3045 (1992), Nephrol Dial Transplant, 10: 787-795 (1995), Kidney International, 43 (Suppl. 39): 86-89 (1993), Journal of Rheumatology, 21: 1507-1511 (1994), Scandinavian Journal of Immunology, 27: 285-294 (1988), etc.].
Regarding nitrogen-containing heterocyclic compounds useful as medicaments, for example, N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamide is disclosed as a bronchodilator in South African Patent 67 06512 (1968). Also, pyrrolo[3,2-d]pyrimidine derivatives are disclosed in Khimiko-Farmatsveticheskij Zhurnal, 16: 1338-1343 (1982) as antibacterial agents, quinoline derivatives having benzodiazepine receptor agonistic activity are disclosed in Pharmacology Biochemistry and Behavior, 53: 87-97 (1996) and European Journal of Medicinal Chemistry, 31: 417-425 (1996), and quinoline derivatives useful as anti-parasitic agents are disclosed in Indian Journal of Chemistry, 26B: 550-555 (1987).
Also, regarding PDGF receptor phosphorylation inhibitors, bismono- and bicyclic aryl and heteroaryl compounds are disclosed in WO 92/20642, and quinoxaline derivatives in Cancer Research, 54: 6106 (1994), pyrimidine derivatives in Japanese Published Unexamined Patent Application No. 87834/94, quinoline derivatives and quinazoline derivatives in WO 97/17329, pyrido[2,3-d]pyrimidine derivatives in J. Med. Chem., 40: 2296 (1997), etc. and selenium derivatives in J. Med. Chem., 40: 413 (1997).
Inhibitors of phosphorylation of epidermal growth factor (EGF) receptor family are disclosed, for example, in Japanese Published Unexamined Patent Application No. 208911/93, WO 96/09294, WO 96/31510 and WO 97/13771. Tricyclic system nitrogen-containing heterocyclic compounds disclosed in WO 95/19970 and pyridopyrimidine derivatives disclosed in J. Med. Chem., 39: 1823 (1996), for example, are known as compounds having the activity inhibiting phosphorylation of a receptor of EGF which is a tyrosine kinase. Also, as inhibitors of phosphorylation of an EGF receptor or EGF receptor family, pyrimidopyrimidine derivatives are disclosed in J. Med. Chem., 40: 1820 (1997), pyrrolo- and pyrazoloquinazoline derivatives are disclosed in J. Med. Chem., 40: 1519 (1997), and pyrrolopyrimidine derivatives are disclosed in WO 96/40142, WO 97/02266, WO 97/27199, EP 682027, etc. In addition, inhibitors of phosphorylation of EGF receptor family are disclosed in Japanese Published Unexamined Patent Application No. 208911/93, WO 96/09294, WO 96/31510, WO 97/13771, etc. All of these compounds are ring-fused pyrimidine derivatives and have a structure in which a simple amino group such as a substituted anilino group, an alkoxy group or the like are linked to the 4-position of the pyrimidine ring.
On the other hand, in the compounds disclosed in the present invention, a structure, such as urea, thiourea, guanidine, amidine, or the like, is linked to a position corresponding to the 4-position of pyrimidine, via substituted or unsubstituted piperazine or homopiperazine, and such a structure is not known as to substances having the activity of inhibiting phosphorylation of EGF receptors and the like.
The present invention relates to a nitrogen-containing heterocyclic compound represented by formula (I): 
wherein W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbon atoms on the ring may be substituted with 1 to 4 alkyl groups which are the same or different;
U represents NR1R2 (wherein R1 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group; and R2 represents a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group, CQR1A (wherein Q represents an oxygen atom or a sulfur atom; and R1A has the same meaning as R1 described above), or SO2R3 (wherein R3 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group)), OR4 (wherein R4 has the same meaning as R3 described above), or SR5 (wherein R5 has the same meaning as R3 described above);
V represents an oxygen atom, a sulfur atom, Nxe2x80x94R6 (wherein R6 has the same meaning as R1 described above or represents a cyano group, a hydroxyl group, a nitro group, a carbamoyl group, COOR3A (wherein R3A has the same meaning as R3 described above), CQAR1B (wherein QA has the same meaning as Q described above, and R1B has the same meaning as R1 described above), or SO2R3B (wherein R3B has the same meaning as R3 described above)), or CR7R8 (wherein R7and R8 are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, COOR3C (wherein R3C has the same meaning as R3 described above), or SO2R3D (wherein R3D has the same meaning as R3 described above)), with the proviso that, when R1 is hydrogen, R6 and R2 may be exchanged, V may represent Nxe2x80x94R2 (wherein R2 has the same meaning as defined above), and R2 may represent R6 (wherein R6 has the same meaning as defined above), and when U is OR4 or SR5, V represents Nxe2x80x94R6 or CR7R8,
at least one of X, Y and Z represents a nitrogen atom, and the others are the same or different, and each represents a nitrogen atom or Cxe2x80x94RA  less than wherein RA has the same meaning as R1 defined above, or represents a halogen atom, a cyano group, a nitro group, NR9R10 {wherein R9 and R10 are the same or different, and each has the same meaning as R1 described above, or represents SO2R3E (wherein R3E has the same meaning as R3 described above) or CQBR11 (wherein Qb has the same meaning as Q described above; and R11 has the same meaning as R1 described above, or represents OR3F (wherein R3F has the same meaning as R3 described above) or NR1CR1D (wherein R1C and R1D are the same or different, and each has the same meaning as R1 described above, or R1C and R1D are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or R9 and R10 are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group}, CQCR11A (wherein QC has the same meaning as Q described above; and R11A has the same meaning as R11 described above), OR12 {wherein R12 has the same meaning as R1 described above, or represents CQDR13 (wherein QD has the same meaning as Q described above; and R13 has the same meaning as R1 described above, or represents OR3G (wherein R3G has the same meaning as R3 described above), SR3H (wherein R3H has the same meaning as R3 described above), or NR1ER1F (wherein R1E and R1F are the same or different, and each has the same meaning as R1 described above, or R1E and R1F are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or SO2R3I (wherein R3I has the same meaning as R3 described above)}, SR1G (wherein R1G has the same meaning as R1 described above), SOR3J (wherein R3J has the same meaning as R3 described above) or SO2R14 (wherein R14 has the same meaning as R3 described above, or represents OR1H (wherein R1H has the same meaning as R1 described above) or NR1IR1J (wherein R1I and R1J are the same or different, and each has the same meaning as R1 described above, or R1I and R1J are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)) greater than , and
(1) when V represents Nxe2x80x94R6 or CR7R8, and U represents NR1R2, OR4, or SR5,
D1, D2, D3 and D4 each independently represent Cxe2x80x94RB (wherein RB has the same meaning as RA described above), a nitrogen atom, an oxygen atom, or a sulfur atom; or optional adjoining two among D1 to D4 may be combined to represent a nitrogen atom, Nxe2x80x94R2A (wherein R2A has the same meaning as R2 described above, or represents an alkyl group or CQENHR3K (wherein QE has the same meaning as Q described above; and R3K has the same meaning as R3 described above)), an oxygen atom, or a sulfur atom, and the remains among D1 to D4 may represent Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as RA described above), Nxe2x80x94R2Axe2x80x2 (wherein R2Axe2x80x2 has the same meaning as R2A described above), or a nitrogen atom; and in these two cases, the optional adjoining two selected from D1 to D4 may represent Cxe2x80x94RBxe2x80x3 (wherein two RBxe2x80x3s, together with the two adjoining carbon atoms, represent substituted or unsubstituted alicyclic alkene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted thiophene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene), and
(2) when V represents an oxygen atom or a sulfur atom, and U represents NR1R2,
(2-1)
at least one of D1 to D4 represents a nitrogen atom, an oxygen atom or a sulfur atom; optional adjoining two among D1 to D4 are combined to represent a nitrogen atom, Nxe2x80x94R2B (wherein R2B has the same meaning as R2 described above), or an oxygen atom; or D2 and D3 are combined to represent a sulfur atom; and in these three cases, the remains among D1 to D4 represent a nitrogen atom, Nxe2x80x94R2Bxe2x80x2 (wherein R2Bxe2x80x2 has the same meaning as R2 described above), an oxygen atom, a sulfur atom, or Cxe2x80x94RC (wherein the RCs each independently have the same meaning as RA described above, or optional two RCs"" adjoining carbon atoms of which are adjacent, together with the two adjoining carbon atoms, may represent substituted or unsubstituted alicyclic alkene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene),
(2-2)
D1 and D2 are combined to represent a sulfur atom; D3 represents Cxe2x80x94RCxe2x80x2 (wherein RCxe2x80x2 has the same meaning as RA described above); and D4 represents a nitrogen atom, or D3 and D4 represent Cxe2x80x94RCxe2x80x3 (wherein RCxe2x80x3s, together with two adjoining carbon atoms, represent substituted or unsubstituted alicyclic alkene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene),
(2-3)
D3 and D4 are combined to represent a sulfur atom; D2 represents Cxe2x80x94RCxe2x80x2xe2x80x3 (wherein RCxe2x80x2xe2x80x3 has the same meaning as RA described above); and D1 represents a nitrogen atom, or D1 and D2 represent Cxe2x80x94RCxe2x80x3xe2x80x3 (wherein RCxe2x80x3xe2x80x3 has the same meaning as RCxe2x80x3 described above), or
(2-4)
D1, D2, D3 and D4 represent Cxe2x80x94RD (wherein in RDs, optional two RDs"" adjoining carbon atoms of which are adjacent, together with the two adjoining carbon atoms, represent substituted or unsubstituted alicyclic alkene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, or substituted or unsubstituted tetrazine, and each of the remaining RDS independently represents the same meaning as RA described above), or a pharmaceutically acceptable salt thereof.
Hereinafter, the compound represented by formula (I) is called compound (I). Compounds represented by other formula numbers are also called in the same manner.
In the definition of each group of formula (I), examples of the alkyl group include straight or branched alkyl groups having from 1 to 16 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, and the like; examples of the alicyclic alkyl group include monocyclic groups having from 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl and polycyclic groups including pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantyl, hexahydro-4,7-methano-1H-indenyl, 4-hexylbicyclo[2.2.2]octyl, and the like; examples of the alicyclic heterocyclic group include tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like; examples of the nitrogen-containing heterocyclic group include pyrrolidinyl, piperidino, piperidinyl, homopiperidino, homopiperidinyl, piperazinyl, homopiperazinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, and the like; examples of the alkenyl group include straight or branched alkenyl groups having from 2 to 16 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, decenyl, dodecenyl, hexadecenyl, and the like; examples of the alkynyl group include straight or branched alkynyl groups having from 2 to 16 carbon atoms, such as ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, decynyl, dodecynyl, hexadecynyl, and the like; examples of the aryl group include phenyl, naphthyl, anthryl, pyrenyl, and the like; examples of the aralkyl group include those having from 7 to 15 carbon atoms, such as benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl, trityl, naphthylmethyl, naphthylethyl, and the like; and examples of the heteroaryl group include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiadiazolyl, benzothienyl, benzofuryl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, purinyl, and the like. The heteroaryl moiety of the heteroarylalkyl group has the same meaning as the heteroaryl group described above, and its alkyl moiety has the same meaning as the alkyl group described above. Examples of the alicyclic alkene include those having from 4 to 12 carbon atoms, such as cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclododecene, and the like. The halogen atom means any atom of fluorine, chlorine, bromine and iodine.
The substituents of the substituted alkyl group, substituted alkenyl group, substituted alkynyl group, substituted alicyclic alkyl group, substituted alicyclic heterocyclic group and substituted alicyclic alkene are the same or different and includes 1 to 3 substituents, such as a nitro group, a cyano group, a hydroxyl group, an oxo group, a halogen atom, an alicyclic alkyl group, an aryl group, an alicyclic heterocyclic group, a carboxyl group, a formyl group, G1xe2x80x94J1xe2x80x94R15 {wherein G1 represents a single bond, an oxygen atom, or a sulfur atom; J1 represents CO, CS, or SO2; and R15 represents an alkyl group, an alicyclic alkyl group, an alicyclic heterocyclic group, an alkenyl group, an alkynyl group, an R16-substituted aryl group (wherein R16 represents an alkyl group, a nitro group, a cyano group, a hydroxyl group, a halogen atom, or NR17R18 (wherein R17 and R18 are the same or different, and each represents a hydrogen atom, an alkyl group, an alicyclic alkyl group, an alicyclic heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroarylalkyl group, or R17 and R18 are combined to represent a nitrogen-containing heterocyclic group)) or an unsubstituted aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, an alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, an alicyclic alkoxy group, an O-alicyclic hetero ring-substituted hydroxyl group, an alkenyloxy group, an alkynyloxy group, an R16-substituted aryloxy group (wherein R16 has the same meaning as defined above) or an unsubstituted aryloxy group, an aralkyloxy group, a heteroaryloxy group, a heteroarylalkoxy group, an amino group, an alkylamino group, an alicyclic alkylamino group, an R19-substituted N-alicyclic hetero ring-substituted amino group (wherein R19 represents a hydroxyl group, an oxo group, or NR20R21 (wherein R20 and R21 are the same or different, and each represents a hydrogen atom, an alkyl group, an alicyclic alkyl group, an alicyclic heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroarylalkyl group, or R20 and R21 are combined to represent a nitrogen-containing heterocyclic group)) or an unsubstituted N-alicyclic hetero ring-substituted amino group, an alkenylamino group, an alkynylamino group, an R16-substituted arylamino group (wherein R16 has the same meaning as defined above) or an unsubstituted arylamino group, an aralkylamino group, a heteroarylamino group, or a heteroarylalkylamino group}, NR22R23 (wherein R22 and R23 are the same or different, and each represents a hydrogen atom, an alkyl group, an alicyclic alkyl group, an alicyclic heterocyclic group, an alkenyl group, an alkynyl group, an R16-substituted aryl group (wherein R16 has the same meaning as defined above) or an unsubstituted aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, an alkanoyl group, an alicyclic alkanoyl group, an alicyclic heteroring-carbonyl group, an alkenoyl group, an alkynoyl group, an R16-substituted aroyl group (wherein R16 has the same meaning as defined above) or an unsubstituted aroyl group, an aralkylcarbonyl group, a heteroarylcarbonyl group, a heteroarylalkylcarbonyl group, an alkoxycarbonyl group, an alicyclic alkoxycarbonyl group, an O-alicyclic hetero ring-substituted hydroxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an R16-substituted aryloxycarbonyl group (wherein R16 has the same meaning as defined above) or an unsubstituted aryloxycarbonyl group, an aralkyloxycarbonyl group, a heteroaryloxycarbonyl group, a heteroarylalkoxycarbonyl group, an alkylsulfonyl group, an alicyclic alkylsulfonyl group, an alicyclic heteroring-sulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, an R16-substituted arylsulfonyl group (wherein R16 has the same meaning as defined above) or an unsubstituted arylsulfonyl group, an aralkylsulfonyl group, a heteroarylsulfonyl group, a heteroarylalkylsulfonyl group, or xe2x80x94CQFNR17AR18A (wherein QF represents an oxygen atom or a sulfur atom; and R17A and R18A have the same meanings as R17 and R18 defined above), or R22 and R23 are comb nitrogen-containing heterocyclic group), an alkoxy group, an alicyclic alkoxy group, an O-alicyclic hetero ring-substituted hydroxyl group, an alkenyloxy group, an alkynyloxy group, an R16-substituted aryloxy group (wherein R16 has the same meaning as defined above) or an unsubstituted aryloxy group, an aralkyloxy group, a heteroaryloxy group, a heteroarylalkoxy group, a sulfo group, a trifluoromethylthio group, an alkylthio group, an alicyclic alkylthio group, an alicyclic heteroring-thio group, an alkenylthio group, an alkynylthio group, an R16-substituted arylthio group (wherein R16 has the same meaning as defined above) or an unsubstituted arylthio group, an aralkylthio group, a heteroarylthio group, a heteroarylalkylthio group, a trifluoromethylsulfinyl group, an alkylsulfinyl group, an alicyclic alkylsulfinyl group, an alicyclic heteroring-sulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, an R16-substituted arylsulfinyl group (wherein R16 has the same meaning as defined above) or an unsubstituted arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, a heteroarylalkylsulfinyl group, and the like.
The substituents of the substituted nitrogen-containing heterocyclic group, substituted aryl group, substituted aralkyl group, substituted heteroaryl group, substituted heteroarylalkyl group, substituted pyrrole, substituted pyrazole, substituted imidazole, substituted imidazol-2-one, substituted imidazole-2-thione, substituted triazole, substituted furan, substituted 1,3-dioxole, substituted 1,4-dioxene, substituted thiophene, substituted oxazole, substituted oxadiazole, substituted isoxazole, substituted thiazole, substituted isothiazole, substituted thiadiazole, substituted pyridine, substituted pyrazine, substituted pyrimidine, substituted pyridazine, substituted triazine, substituted tetrazine and substituted phenyl are the same or different, and includes 1 to 3 substituents, such as a nitro group, a cyano group, a hydroxyl group, a halogen atom, a methylenedioxy group, (OCH2CH2)nO (wherein n is an integer of 1 to 6), a trimethylene group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, an azido group, a thiocyanato group, an R19-substituted alkyl group (wherein R19 has the same meaning as defined above) or an unsubstituted alkyl group, an R16-substituted alicyclic alkyl group (wherein R16 has the same meaning as defined above) or an unsubstituted alicyclic alkyl group, an alicyclic heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a carboxyl group, a formyl group, G1xe2x80x94J1xe2x80x94R15 (wherein G1, J1 and R15 have the same meanings as defined above), NR22R23 (wherein R22 and R23 have the same meanings as defined above), an alkoxy group, an alicyclic alkoxy group, an O-alicyclic hetero ring-substituted hydroxyl group, an alkenyloxy group, an alkynyloxy group, an R16-substituted aryloxy group (wherein R16 has the same meaning as defined above) or an unsubstituted aryloxy group, an aralkyloxy group, a heteroaryloxy group, a heteroarylalkoxy group, a sulfo group, a trifluoromethylthio group, an alkylthio group, an alicyclic alkylthio group, an alicyclic-heteroring-thio group, an alkenylthio group, an alkynylthio group, an R16-substituted arylthio group (wherein R16 has the same meaning as defined above) or an unsubstituted arylthio group, an aralkylthio group, a heteroarylthio group, a heteroarylalkylthio group, a trifluoromethylsulfinyl group, an alkylsulfinyl group, an alicyclic alkylsulfinyl group, an alicyclic heteroring-sulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, an R16-substituted arylsulfinyl group (wherein R16 has the same meaning as defined above) or an unsubstituted arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, a heteroarylalkylsulfinyl group, an R16-substituted arylazo group (wherein R16 has the same meaning as defined above) or an unsubstituted arylazo group, a heteroarylazo group, and the like.
In the above definition of each substituent, the alkyl moiety of the alkoxy group, alkylamino group, alkanoyl group, alkoxycarbonyl group, alkylthio group and alkylsulfinyl group has the same meaning as the alkyl group described above; the alicyclic alkyl moiety of the alicyclic alkoxy group, alicyclic alkylamino group, alicyclic alkanoyl group, alicyclic alkoxycarbonyl group, alicyclic alkylsulfonyl group, alicyclic alkylthio group and alicyclic alkylsulfinyl group has the same meaning as the alicyclic alkyl group described above; the alicyclic hetero ring moiety of the O-alicyclic hetero ring-substituted hydroxyl group, N-alicyclic hetero ring-substituted amino group, alicyclic heteroring-carbonyl group, O-alicyclic hetero ring-substituted hydroxycarbonyl group, alicyclic heteroring-sulfonyl group, alicyclic heteroring-thio group and alicyclic heteroring-sulfinyl group has the same meaning as the alicyclic heterocyclic group described above; the alkenyl moiety of the alkenyloxy group, alkenylamino group, alkenoyl group, alkenyloxycarbonyl group, alkenylsulfonyl group, alkenylthio group and alkenylsulfinyl group has the same meaning as the alkenyl group described above; the alkynyl moiety of the alkynyloxy group, alkynylamino group, alkynoyl group, alkynylsulfonyl group, alkynylthio group and alkynylsulfinyl group has the same meaning as the, alkynyl group described above; the aryl moiety of the aryloxy group, arylamino group, aroyl group, aryloxycarbonyl group, arylsulfonyl group, arylthio group, arylsulfinyl group and arylazo group has the same meaning as the aryl group described above; the aralkyl moiety of the aralkyloxy group, aralkylamino group, aralkylcarbonyl group, aralkyloxycarbonyl group, aralkylsulfonyl group, aralkylthio group and aralkylsulfinyl group has the same meaning as the aralkyl group described above; the heteroaryl moiety of the heteroaryloxy group, heteroarylamino group, heteroarylcarbonyl group, heteroaryloxycarbonyl group, heteroarylsulfonyl group, heteroarylthio group, heteroarylsulfinyl group and heteroarylazo group has the same meaning as the heteroaryl group described above; and the heteroarylalkyl moiety of heteroarylalkoxy group, heteroarylalkylamino group, heteroarylalkylcarbonyl group, heteroarylalkoxycarbonyl group, heteroarylalkylsulfonyl group, heteroarylalkylthio group and heteroarylalkylsulfinyl group has the same meaning as the heteroarylalkyl group described above. Also, the alicyclic alkyl group, aryl group, alicyclic heterocyclic group, alkyl group, alkenyl group, alkynyl group, halogen atom, aralkyl group, heteroaryl group, heteroarylalkyl group and nitrogen-containing heterocyclic group have the same meanings as described above, respectively.
As preferred embodiments of the present invention, nitrogen-containing heterocyclic compounds wherein W represents 1,4-piperazinediyl or pharmaceutically acceptable salts thereof can be exemplified. Particularly, compounds wherein at least one of X and Z represents a nitrogen atom, and Y represents Cxe2x80x94RA (wherein RA has the same meaning as defined above) are preferred, and compounds wherein X and Z represent nitrogen atoms, and RA represents a hydrogen atom or NR9R10 (wherein R9 and R10 have the same meanings as defined above) are preferred. Further, nitrogen-containing heterocyclic compounds wherein U is NR1R2 (wherein R1 and R2 have the same meanings as defined above) or pharmaceutically acceptable salts thereof are preferred.
Among these nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, in preferred compounds, R1 represents a hydrogen atom; and R2 represents a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group, and more preferably, R2 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group.
In addition, the following nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof are excellent among the above preferred embodiments.
Preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents Nxe2x80x94R6 (wherein R6 has the same meaning as defined above); and
1) D1 and D2 are combined to represent Nxe2x80x94R2A (wherein R2A has the same meaning as defined above); and D3 and D4 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above),
2) D1 and D2 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D3 and D4 are combined to represent Nxe2x80x94R2A (wherein R2A has the same meaning as defined above),
3) D1 and D4 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D2 and D3 are combined to represent Nxe2x80x94R2A (wherein R2A has the same meaning as defined above),
4) D1 represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); D2 and D3 are combined to represent a nitrogen atom; and D4 represents Nxe2x80x94R2Axe2x80x2 (wherein R2Axe2x80x2 has the same meaning as defined above),
5) D4 represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); D2 and D3 are combined to represent a nitrogen atom; and D1 represents Nxe2x80x94R2Axe2x80x2 (wherein R2Axe2x80x2 has the same meaning as defined above),
6) D1 and D2 are combined to represent Nxe2x80x94R2A (wherein R2A has the same meaning as defined above); D3 represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D4 represents a nitrogen atom,
7) D1 and D2 are combined to represent a nitrogen atom; D3 represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D4 represents Nxe2x80x94R2Axe2x80x2 (wherein R2Axe2x80x2 has the same meaning as defined above),
8) D1, D2 and D3 each independently represents Cxe2x80x94RB (Wherein RB has the same meaning as defined above); and D4 represents a nitrogen atom,
9) D1, D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D3 represents a nitrogen atom,
10) D1, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 represents a nitrogen atom,
11) D2, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D1 represents a nitrogen atom,
12) D1 and D3 represent nitrogen atoms; and D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above),
13) D1 and D3 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 and D4 represent nitrogen atoms,
14) D1 and D2 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D3 and D4 represent nitrogen atoms,
15) D1 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 and D3 represent nitrogen atoms,
16) D3 and D4 each independently represent Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D1 and D2 represent nitrogen atoms,
17) D2 and D3 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D1 and D4 represent nitrogen atoms,
18) D1, D2, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above),
19) D1 and D2 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D3 and D4 are combined to represent a sulfur atom,
20) D1 and D4 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D2 and D3 are combined to represent a sulfur atom, or
21) D3 and D4 each independently represents Cxe2x80x94RBxe2x80x2(wherein RBxe2x80x2 has the same meaning as defined above); and D1 and D2 are combined to represent a sulfur atom.
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents an oxygen atom or a sulfur atom; and
1) D1 and D2 are combined to represent Nxe2x80x94R2B (wherein R2B has the same meaning as defined above); and D3 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above),
2) D1 and D2 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D3 and D4 are combined to represent Nxe2x80x94R2B (wherein R2B has the same meaning as defined above),
3) D1 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D2 and D3 are combined to represent Nxe2x80x94R2B (wherein R2B has the same meaning as defined above),
4) D1 represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); D2 and D3 are combined to represent a nitrogen atom; and D4 represents Nxe2x80x94R2Bxe2x80x2 (wherein R2Bxe2x80x2 has the same meaning as defined above),
5) D4 represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); D2 and D3 are combined to represent a nitrogen atom; and D1 represents Nxe2x80x94R2Bxe2x80x2xe2x80x2(wherein R2Bxe2x80x2 has the same meaning as defined above),
6) D1 and D2 are combined to represent Nxe2x80x94R2B (wherein R2B has the same meaning as defined above); D3 represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D4 represents a nitrogen atom,
7) D1 and D2 are combined to represent a nitrogen atom; D3 represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D4 represents Nxe2x80x94R2Bxe2x80x2 (wherein R2Bxe2x80x2 has the same meaning as defined above),
8) D1, D2 and D3 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D4 represents a nitrogen atom,
9) D1, D2 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D3 represents a nitrogen atom,
10) D1, D3 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D2 represents a nitrogen atom,
11) D2, D3 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D1 represents a nitrogen atom,
12) D1 and D3 represent nitrogen atoms; and D2 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above),
13) D1 and D3 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D2 and D4 are nitrogen atoms,
14) D1 and D2 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D3 and D4 are nitrogen atoms,
15) D1 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D2 and D3 are nitrogen atoms,
16) D3 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D1 and D2 are nitrogen atoms,
17) D2 and D3 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D1 and D4 are nitrogen atoms,
18) D1, D2, D3 and D4 each independently represents Cxe2x80x94RD (wherein RD has the same meaning as defined above),
19) D1 and D2 each independently represents Cxe2x80x94RCxe2x80x3xe2x80x3 (wherein RCxe2x80x3xe2x80x3 has the same meaning as defined above); and D3 and D4 are combined to represent a sulfur atom,
20) D1 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D2 and D3 are combined to represent a sulfur atom, or
21) D3 and D4 each independently represents Cxe2x80x94RCxe2x80x3 (wherein RCxe2x80x3 has the same meaning as defined above); and D1 and D2 are combined to represent a sulfur atom.
Also, preferred examples include nitrogen-containing heterocyclic compound or pharmaceutically acceptable salts thereof, wherein V represents Nxe2x80x94CN; and
1) D1 and D2 are combined to represent a nitrogen atom; D3 represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D4 represents Nxe2x80x94R2Axe2x80x2 (wherein R2Axe2x80x2 has the same meaning as defined above),
2) D1, D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D3 represents a nitrogen atom, or
3) D1, D2, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above).
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents Nxe2x80x94CN; and
D1 and D2 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D3 and D4 are combined to represent Nxe2x80x94R2A (wherein R2A has the same meaning as defined above).
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents Nxe2x80x94CN; and
1) D1, D2 and D3 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D4 represents a nitrogen atom,
2) D1, D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D3 represents a nitrogen atom,
3) D1, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 represents a nitrogen atom, or
4) D2, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D1 represents a nitrogen atom.
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents Nxe2x80x94CN; and
1) D1 and D3 represent nitrogen atoms; and D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above), or
2) D1 and D3 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 and D4 represent nitrogen atoms.
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents an oxygen atom or a sulfur atom; and
1) D1 and D2 are combined to represent a nitrogen atom; D3 represents Cxe2x80x94RC (wherein RC has the same meaning as defined above); and D4 represents Nxe2x80x94R2Bxe2x80x2 (wherein R2Bxe2x80x2 has the same meaning as defined above),
2) D1, D2 and D4 each independently represents Cxe2x80x94RC (wherein RC has the same-meaning as defined above); and D3 represents a nitrogen atom, or
3) D1, D2, D3 and D4 each independently represents Cxe2x80x94RD (wherein RD has the same meaning as defined above).
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents an oxygen atom or a sulfur atom; and
D1 and D2 each independently represents Cxe2x80x94RBxe2x80x2 (wherein RBxe2x80x2 has the same meaning as defined above); and D3 and D4 are combined to represent Nxe2x80x94R2A (wherein R2A has the same meaning as defined above).
Also preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents an oxygen atom or a sulfur atom; and
1) D1, D2 and D3 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D4 represents a nitrogen atom,
2) D1, D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D3 represents a nitrogen atom,
3) D1, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 represents a nitrogen atom, or
4) D2, D3 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D1 represents a nitrogen atom.
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents an oxygen atom or a sulfur atom; and
1) D1 and D3 represent nitrogen atoms; and D2 and D4 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above), or
2) D1 and D3 each independently represents Cxe2x80x94RB (wherein RB has the same meaning as defined above); and D2 and D4 represent nitrogen atoms.
Also, preferred examples include nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof, wherein V represents an oxygen atom or a sulfur atom; D1, D2, D3 and D4 represent Cxe2x80x94RD (wherein RD has the same meaning as defined above); and optional two RDs"" adjoining carbon atoms of which are adjacent, together with the two adjoining carbon atoms, represent substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, or substituted or unsubstituted pyrazine.
In order to explain preferred embodiments of the present invention more specifically, some chemical structures in Compound (I) are exemplified below. The present invention is characterized by the substituent, W(C=V)U (wherein W, V and U have the same meanings as defined above, respectively) of Compound (I) as a matter of course, and this substituent binds to a bicyclic or tricyclic hetero ring represented by D1, D2, D3, D4, X, Y, Z and two carbon atoms , which is also a characteristic of the present invention, at the position shown in formula (I). Compounds in which X and Z each represents a nitrogen atom are one of the preferred embodiments, and compounds in which corresponding quinazoline or pyrimidine forms a condensed polycyclic hetero ring system are exemplified as group names below.
Examples of the group showing a preferred ring structure include pyrrolo[3,2-g]quinazolinyl, pyrazino[2,3-g]quinazolinyl, benzothieno[3,2-d]pyrimidinyl, thiazolo[5xe2x80x2,4xe2x80x2;4,5]thieno[3,2-d]pyrimidinyl, pyrido[2xe2x80x2,3xe2x80x2;4,5]thieno[3,2-d]pyrimidinyl, indolo[3,2-d]pyrimidinyl, indolo[2,3-d]pyrimidinyl, benzofurano[3,2-d]pyrimidinyl, pyrimido[4,5-f]quinazolinyl, benzothieno[2,3-d]pyrimidinyl, thieno[2xe2x80x2,3xe2x80x2;4,5]thieno[3,2-d]pyrimidinyl, thieno[3xe2x80x2,2xe2x80x2;4,5]thieno[2,3-d]pyrimidinyl, imidazo[5xe2x80x2,4xe2x80x2;4,5]thieno[3,2-d]pyrimidinyl, pyrido[3xe2x80x2,2xe2x80x2;4,5]thieno[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, purinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrimidino[5,4-d]pyrimidinyl, pyrimidino[4,5-d]pyrimidinyl, pyrrolo[3,2-g]quinazolinyl, pyrrolo[2,3-f]quinazolinyl, pyrazolo[4,3-g]quinazolinyl, pyrazolo[3,4-g]quinazolinyl, furo[2,3-d]pyrimidinyl, furo[3,4-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, triazolo[4,5-d]pyrimidinyl, and the like, though preferred ring structures of the present invention are not limited thereto.
Examples of the pharmaceutically acceptable salt of Compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of the pharmaceutically acceptable acid addition salt of Compound (I) include inorganic acid salts, such as hydrochloride, sulfate, phosphate, and the like, and organic acid salts, such as acetate, maleate, fumarate, tartrate, citrate, methanesulfonate, and the like; examples of the pharmaceutically acceptable metal salt include alkali metal salts, such as sodium salt, potassium salt, and the like, alkaline earth metal salts, such as magnesium salt, calcium salt, and the like, aluminum salt, zinc salt, and the like; examples of the pharmaceutically acceptable ammonium salt include salts such as ammonium, tetramethylammonium, and the like; examples of the pharmaceutically acceptable organic amine addition salt include addition salts of morpholine, piperidine, and the like; and examples of the pharmaceutically acceptable amino acid addition salt include addition salts of lysine, glycine, phenylalanine, and the like.
Next, processes for producing Compound (I) are described.
Production Process 1
Compound (I-a), wherein U represents NHR2; and V represents an oxygen atom or a sulfur atom, can be produced according to the following reaction step. 
(In the formulae, D1, D2, D3, D4, R2, W, X, Y and Z have the same meanings as defined above, respectively; Vxe2x80x2 represents an oxygen atom or a sulfur atom; and Wxe2x80x2 represents 1-piperazinyl or 1-homopiperazinyl in which carbons on the ring may be substituted with 1 to 4 alkyl groups which are the same or different.)
Compound (I-a) can be obtained by allowing Compound (II) to react with an isocyanate (R2xe2x80x94Nxe2x95x90Cxe2x95x90O) which is commercially available or can be obtained by a known process [for example, Organic Functional Group Preparations, S. R. Sandler et al., 1: 305, Academic Press Inc., New York and London (1968), Synthetic Organic Chemistry, R. B. Wagner et al., 3rd ed., p. 640, John Wiley (1961), etc.] or with an isothiocyanate (R2xe2x80x94Nxe2x95x90Cxe2x95x90S) [e.g., Organic Functional Group Preparations, S. R. Sandler et al., 1: 312, Academic Press Inc., New York and London (1968), Synthetic Organic Chemistry, R. B. Wagner et al., 3rd ed., p. 829, John Wiley (1961), etc.] at a temperature between xe2x88x9220xc2x0 C. and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent,, such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol, isopropanol, etc., an aprotic polar solvent, such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixed solvent thereof, optionally in the presence of a base, for example, an organic base, such as triethylamine, pyridine, etc., an inorganic base, such as potassium carbonate, sodium. hydroxide, sodium hydride, etc., a metal alkoxide, such as sodium methoxide, potassium tert-butoxide, etc., or the like.
Compound (II) as the starting material can be obtained by the process disclosed in Japanese Published Unexamined Patent Application No. 104074/89, South African Patent 67 06512, Ind. J. Chem., 26B: 550-555 (1987), or the like, or a modified process thereof, or can also be obtained by a process of the following reaction scheme. 
(In the formulae, D1, D2, D3, D4, Wxe2x80x2, X, Y and Z have the same meanings as defined above, respectively; and L1 represents a leaving group.)
Examples of the leaving group in the definition of L1 include halogen atoms, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted alkylthio groups, substituted or unsubstituted alkylsulfinyl groups, substituted or unsubstituted alkylsulfonyl groups, substituted or unsubstituted alkylsulfonyloxy groups, substituted or unsubstituted arylsulfonyloxy groups, and the like. The halogen atom, alkoxy group, aryloxy group, alkylthio group and alkylsulfinyl group have the same meanings as defined above, respectively, the alkyl moiety of the alkylsulfonyl group and alkylsulfonyloxy group has the same meaning as the alkyl group defined above, and the aryl moiety of the arylsulfonyloxy group has the same meaning as the aryl defined above. Examples of the substituent include halogen atoms, alkyl groups, a nitro group, and the like, and the halogen atom has the same meaning as the halogen atom defined above.
Compound (II) can be obtained by allowing Compound (III) to react with a compound Wxe2x80x2xe2x80x94H at a temperature between room temperature and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a lower alcohol, such as methanol, ethanol, isopropanol, etc., a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent, such as diethyl ether, THF, 1,4-dioxane, etc., an aprotic polar solvent, such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixed solvent thereof, optionally in the presence of a base. Examples of the base include organic bases, such as triethylamine, pyridine, etc., inorganic bases, such as potassium carbonate, sodium hydroxide, sodium hydride, etc., metal alkoxides, such as sodium methoxide, potassium tert-butoxide, etc., and the like.
When the group defined in the above production process changes under conditions of the practical process or is inappropriate for carrying out the process, the objective compound can be obtained by introducing the compound Wxe2x80x2xe2x80x94H, after its protection excluding the reaction point, into Compound (III) and then carrying out deprotection. Examples of the protecting group include protecting groups disclosed in Protective Groups in Organic Synthesis, T. W. Green, John Wiley and Sons Inc. (1981) and the like, such as ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the like. Introduction and elimination of the protecting group can be carried out by a process commonly used in the synthetic organic chemistry (e.g., a process disclosed in the above Protective Groups in Organic Synthesis can be referred to).
A commercially available compound can be used as Compound (III) as the starting material, or Compound (III) as the starting material can be produced by the process disclosed in WO 95/19970, J. Med. Chem., 38: 3780-3788 (1995), J. Med. Chem., 39: 918-928 (1996), J. Med. Chem., 39: 1823-1835 (1996), J. Med. Chem., 40: 1519-1529 (1997), J. Med. Chem., 40: 1820-1826 (1997), Bioorg. Med. Chem. Lett., 5: 2879-2884 (1995), J. Chem. Soc., pp. 890-899 (1947), J. Chem. Soc., pp. 561-572 (1962), J. Chem. Soc., B, pp. 449-454 (1967), J. Indian Chem. Soc., 36: 787-791 (1959), J. Org. Chem., 17: 1571-1575 (1952), J. Med. Chem., 14: 1060-1066 (1971), French Patent 1388756, J. Am. Chem. Soc., 68: 1204-1208 (1946), Ind. J. Chem., 26B: 550-555 (1987), Japanese Published Unexamined Patent Application No. 120872/85, South African Patent 67 06512, or the like, the process described in Reference Examples, or a modified process thereof.
Production Process 2
Compound (I) can be produced according to the following reaction step. 
(In the formulae, L2 has the same meaning as L1 described above; and D1, D2, D3, D4, U, V, W, Wxe2x80x2, X, Y and Z have the same meanings as defined above, respectively.)
Compound (I) can be produced by allowing Compound (II) to react with Compound (IV) at a temperature between xe2x88x9220xc2x0 C and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent, such as diethyl ether, THF, 1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol, isopropanol, etc., an aprotic polar solvent, such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixed solvent thereof, optionally in the presence of a base. Examples of the base include organic. bases, such as triethylamine, pyridine, etc., inorganic bases, such as potassium carbonate, sodium hydroxide, sodium hydride, etc., metal alkoxides, such as sodium methoxide, potassium tert-butoxide, etc., and the like.
A commercially available product can be used as Compound (IV) as the starting material, or Compound (IV) as the starting material can be produced by the process described in Beilstein, 4: 73 (1922), Beilstein, 4: 75 (1922), Bioorg. Med. Chem. Lett., 17: 3095-3100 (1997), J. Med. Chem., 38: 3236-3245 (1995), Japanese Published Unexamined Patent Application No. 18557/78, Jikken Kagaku Koza 20xe2x80x94Yuki Gosei II, 4th ed., p. 355, The Chemical Society of Japan, Maruzen (Tokyo) (1992), Methoden der Organischen Chemie, vol. E11, Organische Schwefel-Verbindungen, Dieter Klamann, p. 263, Georg Thieme Verlag (Stuttgart, New York) (1985), or the like, or a modified process thereof.
Production Process 3
Compound (I) can also be produced according to the following reaction step. 
(In the formulae, L1, D1, D2, D3, D4, U, V, W, Wxe2x80x2, X, Y and Z have the same meanings as defined above, respectively.)
Compound (I) can be produced by allowing Compound (III) to react with Compound (V) at a temperature between room temperature and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent, such as diethyl ether, THF, 1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol, isopropanol, etc., an aprotic polar solvent, such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixed solvent thereof, optionally in the presence of a base. Examples of the base include organic bases, such as triethylamine, pyridine, etc., inorganic bases, such as potassium carbonate, sodium hydroxide, sodium hydride, etc., metal alkoxides, such as sodium methoxide, potassium tert-butoxide, etc., and the like.
Compound (V) as the starting material can be produced by the process disclosed in Examples or Reference Examples or a modified process thereof.
Production Process 4
Compound (I) can also be produced according to the following reaction step. 
(In the formulae, L3 has the same meaning as L1 described above; and D1, D2, D3, D4, U, V, W, X, Y and Z have the same meanings as defined above, respectively.)
Compound (I) can be produced by allowing Compound (VI) to react with a compound U-H at a temperature between room temperature and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent, such as diethyl ether, THF, 1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol, isopropanol, etc., an aprotic polar solvent, such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixed solvent thereof, optionally in the presence of a base. Examples of the base include organic bases, such as triethylamine, pyridine, etc., inorganic bases, such as potassium carbonate, sodium hydroxide, sodium hydride, etc., metal alkoxides, such as sodium methoxide, potassium tert-butoxide, etc., and the like.
Compound (VI) as the starting material can be produced by the process disclosed in South African Patent 67 06512, U.S. Pat. No. 3,723,434, Japanese Published Unexamined Patent Application No. 18557/78, or the like, or a modified process thereof.
Production Process 5
Compound (I-b), wherein U represents NHR2; and V represents Nxe2x80x94R6, can also be produced according to the following reaction step. 
(In the formulae, L4 has the same meaning as L1 defined above; and D1, D2, D3, D4, R2, R6, W, X, Y and Z have the same meanings as defined above, respectively.)
Compound (I-b) can be produced by allowing Compound (VII) to react with a compound R6xe2x80x94NH2 at a temperature between room temperature and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent, such as diethyl ether, THF, 1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol, isopropanol, etc., an aprotic polar solvent, such as pyridine, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc., or a mixed solvent thereof; optionally in the presence of a base. Examples of the base include organic bases, such as triethylamine, pyridine, etc., inorganic bases, such as potassium carbonate, sodium hydroxide, sodium hydride, etc., metal alkoxides, such as sodium methoxide, potassium tert-butoxide, etc., and the like.
Compound (VII) as the starting material can be obtained by the process disclosed in Japanese Published Unexamined Patent Application No. 19671/77, Organic Functional Group Preparations, S. R. Sandler et al., 2: 166-185, Academic Press Inc., New York and London (1971), or the like, or a modified process thereof.
Production Process 6
Compound (I-c), wherein U represents NR1R2; and V represents Nxe2x80x94CN, can also be produced according to the following reaction step. 
(In the formulae, D1, D2, D3, D4, R1, R2, Vxe2x80x2, W, X, Y and Z have the same meanings as defined above, respectively.)
Compound (I-c) can be produced by allowing Compound (I-d) to react with cyanamide at a temperature between room temperature and the boiling point of a used solvent for 10 minutes to 48 hours in an appropriate inert solvent, for example, a halogenated hydrocarbon, such as chloroform, dichloromethane, etc., an aromatic hydrocarbon, such as benzene, toluene, etc., an ether solvent, such as diethyl ether, THF, 1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol, isopropanol, etc., an aprotic polar solvent, such as pyridine, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine, acetonitrile, etc., or a mixed solvent thereof, in the presence of an appropriate condensing agent, such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or the like, and optionally in the presence of a base. Examples of the base include organic bases, such as triethylamine, pyridine, etc., inorganic bases, such as potassium carbonate, sodium hydroxide, sodium hydride, etc., metal alkoxides, such as sodium methoxide, potassium tert-butoxide, etc., and the like.
Furthermore, Compound (I-b) can also be obtained by allowing Compound (II) to react with various carbodiimide compounds under conditions similar to those in Production Process 1. In addition to the commercially available product, the carbodiimide used in the reaction can be produced by the process disclosed in Shin-Jikken Kagaku Koza 14xe2x80x94Yukikagobutu no Gosei to Hanno (III), The Chemical Society of Japan, pp. 1644-1652, Maruzen (Tokyo) (1978), Synthetic Communications, 25: 43-47 (1995), or the like, or a modified process thereof.
When the group defined in each of the above production processes changes under conditions of the practical process or is inappropriate for carrying out the process, the objective compound can be produced by using protecting group introduction and elimination processes commonly used in the synthetic organic chemistry [e.g., see Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons Inc. (1981)]. Furthermore, a conversion of the functional group contained in each substituent can also be carried out by a commonly known process [e.g., Comprehensive Organic Transformations, R. C. Larock (1989), etc.] in addition to the production processes described above, and novel Compound (I) can also be derived by using some of Compounds (I) as a synthetic intermediate.
The intermediate and the objective compound in each of the above production processes can be isolated and purified by subjecting them to purification processes ordinary used in the synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, and the like. Furthermore, the intermediates can also be used in the subsequent reaction without carrying out particular purification.
Regio isomers, geometrical isomers, optical isomers or tautomers may be present for some of Compounds (I), and all possible isomers including them and mixtures thereof are included in the scope of the present invention.
In production of a salt of Compound, (I), when Compound (I) is produced in a salt form, it can be purified as such, and when it is produced in its free form, its salt can be formed in the usual way by dissolving or suspending it in an appropriate organic solvent and adding thereto an acid or a base.
In addition, Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of addition products with water or various solvents, and these addition products are also included in the scope of the present invention.
Examples of Compound (I) obtained by the above production processes are shown in Table 1.
Next, the pharmacological activity of the compounds of the present invention are specifically explained by test examples.
PDGF Receptor Phosphorylation Inhibition Test
This test was carried out according to the process disclosed in a literature [J. Biol. Chem., 266: 413-418 (1991)]. In this case, Chinese hamster ovary (CHO) cells to which human xcex2-PDGF receptor cDNA had been inserted and in which it had been expressed were used in the test. The test results were represented by a concentration at which the test compound inhibits 50% of the PDGF receptor phosphorylation (IC50).
The results are shown in Table 2.
Test results on Compounds 22, 50, 52, 63 and 66 were represented by a ratio (%) of inhibiting phosphorylation of the PDGF receptor at 10 xcexcM, with the results shown in Table 3.
Although Compound, (I) or a pharmaceutically acceptable salt thereof can be administered directly as such, generally, it is preferred to provide it in various forms of pharmaceutical preparations. Further, such pharmaceutical preparations are used for animals and humans.
As their route of administration, it is preferred to use the most effective way in carrying out the treatment, and examples include oral administration and parenteral administration, such as rectal, buccal, subcutaneous, intramuscular, intravenous, and the like.
Examples of the dosage form include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections, and the like.
Liquid preparations suitable for oral administration, such as emulsions or syrups, can be produced using water, saccharides, such as sucrose, sorbitol, fructose, etc., glycols, such as polyethylene glycol, polypropylene glycol, etc., oils, such as sesame oil, olive oil, soybean oil, etc., antiseptics, such as p-hydroxybenzoic acid esters, etc., flavors, such as strawberry flavor, peppermint, etc., and the like. Furthermore, capsules, tablets, powders, granules and the like can be produced using excipients, such as lactose, glucose, sucrose, mannitol, etc., disintegrators, such as starch, sodium alginate, etc ., lubricants, such as magnesium stearate, talc, etc., binders, such as polyvinyl alcohol, hydroxypropylcellulose, gelatin, etc., surfactants, such as fatty acid esters, etc., plasticizers, such as glycerol, etc., and the like.
Preparations suitable for parenteral administration preferably comprise an aqueous sterile preparation containing the active compound which is isotonic with blood of the recipient. For example, in the case of injections, a solution for injection is prepared using a carrier, such as a salt solution, a glucose solution, or a mixture of a brine and a glucose solution, or the like.
Topical preparations are produced by dissolving or suspending the active compound in at least one of media, such as mineral oil, petroleum, polyhydric alcohol, and the like, or in other bases usually used in topical pharmaceutical preparations.
Preparations for rectal administration are produced using usual carriers, such as cacao butter, hydrogenated fat, hydrogenated fat carboxylic acid, and the like, and are provided as suppositories.
Furthermore, at least one auxiliary component selected from the glycols, oils, flavors, antiseptics (including antioxidants), excipients, disintegrators, lubricants, binders, surfactants, plasticizers, and the like which are exemplified in the oral preparations can also be added to these parenteral preparations.
An effective dose and frequency of administration of Compound (I) or a pharmaceutically acceptable salt thereof may vary depending on the dosage form, age and body weight of each patient, properties or seriousness of the symptoms to be treated and the like; however, the dose is generally 0.01 to 1,000 mg/man, preferably 5 to 500 mg/man, per day, and as to the administration frequency, it is preferred to administer it once a day or by dividing the daily dose.
The compounds of the present invention can be directly applied to a therapeutic use as kinase inhibitors, particularly as those which are related to tyrosine kinase, for controlling kinase-dependent diseases in mammals. Compounds having an IC50 value between 10 nM and 10 xcexcM are particularly preferred. It is possible to select a specific compound of the present invention which has the ability of inhibiting selectively one of the three protein kinase (a kinase which phosphorylates tyrosine, a kinase which phosphorylates tyrosine and threonine, and a kinase which phosphorylates threonine). The tyrosine kinase-dependent diseases include over-proliferative malfunctions which are initiated/maintained by abnormal tyrosine kinase enzyme activity. Examples include psoriasis, pulmonary fibrosis, glomerulonephritis, cancers, atherosclerosis, and anti-angiogenesis (e.g., tumor proliferation or diabetic retinopathy). Although relationships of other classes of kinase to specific diseases are not well known, it is considered that a selective tyrosine kinase-inhibiting compound has a useful therapeutic effect. Also, it is understood that other classes of kinase have their own useful therapeutic effects. Quercetin, genistein and staurosporin which are tyrosine kinase inhibitors inhibit many other protein kinase in addition to the tyrosine kinase, and have strong cytotoxicity as a result of the lack of specificity for them. Accordingly, tyrosine kinase inhibitors (or inhibitors of other kinase) which are apt to induce undesirable side effects due to lack of selectivity can be identified using a usual test for measuring cytotoxicity.
Examples, Reference Examples and Formulation Examples of the present invention are shown below; however, the present invention is not limited thereto.